Solvent-free synthesis of 2,4,6-triarylpyridine derivatives promoted by 1,3-dibromo-5,5-dimethylhydantoin

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Solvent-free Synthesis of 2,4,6-
Triarylpyridine Derivatives Promoted by
1,3-Dibromo-5,5-dimethylhydantoin
Behrooz Malekia
a Department of Chemistry, Hakim Sabzevari University, Sabzevar,
Iran
Published online: 18 Mar 2015.
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To cite this article: Behrooz Maleki (2015) Solvent-free Synthesis of 2,4,6-Triarylpyridine Derivatives
Promoted by 1,3-Dibromo-5,5-dimethylhydantoin, Organic Preparations and Procedures International:
The New Journal for Organic Synthesis, 47:2, 173-178, DOI: 10.1080/00304948.2015.1005990
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Organic Preparations and Procedures International, 47:173–178, 2015
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2015.1005990
OPPI BRIEF
Solvent-free Synthesis of 2,4,6-Triarylpyridine
Derivatives Promoted by 1,3-Dibromo-5,5-
dimethylhydantoin
Behrooz Maleki
Department of Chemistry, Hakim Sabzevari University, Sabzevar, Iran
The development of new methods for the synthesis of 2,4,6-triarylpyridines is an impor-
tant area of research because of the broad spectrum of their biological and pharmaceutical
properties such as anti-covulsant, anesthetic, anti-malarial, vasodilator, anti-epileptic
character and their use as pesticidial, fungicidal and herbicidal agro-chemicals.1–3 Due to
their p-stacking ability, some pyridines are used in supramolecular chemistry.4–7 The
2,4,6-triarylpyridine nucleus is structurally related to symmetrical triarylthio-, triarylse-
leno- and triaryltelluoropyrylium salt photosensitizers and has been recommended for
photodynamic cell–specific cancer therapy.8
This wide range of applications has elicited several methods for their prepa-ration.9–
22
Among these, the one-pot reaction of aromatic ketones or aldehydes with ammonium
acetate is one of the simplest and most straightforward approaches. A variety of reagents
such as PEG-400,23 HClO4.SiO2,24 H14[NaP5W30O110],25 molecular iodine,26 microwave
irradiation without catalyst,27 [BmIm][BF4],28 wet 2,4,6-trichloro-1,3,5-triazine (TCT),29
pentafluorophenylammonium triflate,30 trichloroisocyanuric acid,31 bismuth triflate,32
and MgAl2O4 nanocrystals33 have been employed to promote this transformation. Some
of these procedures involve the use of strong corrosive acids or bases, solvents, micro-
wave irradiation, metal salts, high catalyst loading and tedious work-up. Thus the devel-
opment of a new readily available method that avoids many of these problems is highly
desirable.
In recent years, 1,3-dibromo-5,5-dimethylhydantoin (DBH) has been used as a cata-lyst
for a number of reactions34–43 because it is relatively inexpensive, non-toxic, quite stable
and easy to handle. We now report the preparation of 2,4,6-triarylpyridines from aldehydes
and acetophenones by treatment with ammonium acetate in the presence of catalytic
amounts of 1,3-dibromo-5,5- DBH under solvent-free conditions (Scheme 1).
Submitted by August 11, 2014.
Address correspondence to Behrooz Maleki, > Department of Chemistry, Hakim Sabzevari
University, Sabzevar 96179-76487, Iran. E-mail: malekibehrooz@gmail.com
173

174
Maleki
Scheme 1 (Color figure available online.)
We initially examined the condensation of acetophenone (2 mmol), benzaldehyde
(1 mmol) with ammonium acetate (2 mmol) in the presence of 10 mol% (0.1 mmol of
DBH at 120ꢀC under solvent-free conditions. The reaction proceeded rapidly to afford
2,4,6-triphenylpyridine (3a) in high yields (Table 1, Entry 1). Although a lower catalyst
loading led to decreased yields (Entry 2), an increase of the catalyst loading did not im-
prove the yield (Entry 3). A better yield of 3a in a shortened reaction time was obtained
at 100–120ꢀC (Entries 1, 4–5) while the yield unexpectedly decreased to 64% with for-
mation of dark material at 130ꢀ C (Entry 6) possibly due to the decomposition oꢀf the start-
ing compounds or of the product. Thus, all reactions were performed at 120 C in the
presence of 10 mol% of DBH (Table 2). In the absence of the catalyst, no product could
be detected even after 7h (Table 1, Entry 7). The efficiency of various N-halo compounds
was tested under the same conditions. Although NBS, N-chloro-succinimide (NCS) and
1,3-dichloro-5,5-dimethylhydantion (DCH) (Entries 8–10) gave nearly similar yields of
Table 1
Optimization Process
Entry
Catalyst (mol %)
Tem. (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
10
5
120
120
120
110
100
130
120
120
120
120
3.0
4.5
3.5
4.5
6.0
3.5
6.0
3.5
3.5
3.5
90
72
15
10
83
60
10
10
52
64
none
10a
10b
10c
traces
88
76
84
aNBS used in reaction condition; bNCS used in reaction condition; cDCH used in reaction
condition.

Synthesis of 2,4,6-Triarylpyridine Derivatives
175
Table 2
One-pot Synthesis of 2,4,6-Triarylpyridines using 1,3-Dibromo-5,5-dimethylhydantoin
(DBH)
2,4,6-Triarylpyridines
mp (ꢀC)
Found
Entry
3a–t
Yield (%)
Time (h)
Lit.
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
90
86
80
76
87
90
83
86
83
88
92
90
80
89
90
92
91
84
78
82
3
3.5
4
130–132
123–125
156–157
189–190
138–140
177–179
122–123
153–155
201–202
113–115
192–194
101–102
113–115
165–167
199–201
251–253
226–228
195–196
166–168
170–172
132–134
120–122
153–155
190–193
136–138
178–179
119–120
152–154
198–200
112–114
190–191
99–100
2
3
4
4
5
3
6
4
7
3.5
3.5
4
8
9
10
11
12
13
14
15
16
17
18
19
20
3
3
3
3.5
4
114–116
164–166
196–198
248–250
228–230
192–194
164–165
172–174
2.5
3
3
3.5
5
3t
4
3a (Entries 8–10, Table 1), the low cost, ready availability and stability of DBH recom-
mend it as the preferred catalyst for this transformation.
Once these conditions were optimized, the generality of the reaction was examined
with other substrates, using several aromatic aldehydes and ketones in the presence of
10 mol% (0.1 mmol of DBH) at 120ꢀC under solvent-free conditions. The results are
listed in Table 2. The condensation of benzalacetophenone – a possible intermediate –
and 4-methoxyacetophenone with ammonium acetate in the presence of DBH under the
same conditions proceeded smoothly in a shorter time (2.5 h) to give the expected prod-
uct albeit in lower yield (74%). Treatment of propiophenone and butyro-phenone with
benzaldehyde under similar conditions failed to give any product. All these reagents gen-
erate halonium ions that can activate the carbonyl groups of the aldehyde toward nucleo-
philic attack and promote enolization of the ketone as has been shown previously in the
literature.23–32
We have also examined the recyclability of DBH. After the completion of the pre-
paration of 3a, hot EtOH (96%, 1 ml) was added and the solid catalyst separated by filtra-
tion. It was then washed with cold carbon tetrachloride and dried at room temperature for
20 h. Only marginal decreases in the yield of the product 3a were observed in the first
three runs (90, 86, and 82%, respectively) with recycled DBH.
In conclusion, we have described an efficient methodology for the synthesis of 2,4,6-
triarylpyridines under solvent-free conditions. Simple procedures, high yields, easy

176
Maleki
work-up, the avoidance of organic solvents and toxic reagents are significant advantages
of the present method compared to the previous ones. Furthermore, DBH is relatively
inexpensive and stable to air and moisture.
Experimental Section
All reagents and chemicals were purchased from Aldrich, Merck and Fluka and were used
without further purification. IR spectra as KBr pellets were recorded on a Shimadzu 435-
U-04 spectrophotometer. 1H and 13C NMR spectra were obtained using Bruker DRX-300
Avance spectrometer in DMSO-d6 or CDCl3 using TMS as an internal reference. Melting
points were determined in open capillary tubes in a Stuart BI Branstead Electrothermal
Cat No:IA9200 apparatus and uncorrected.
General Procedure for the Synthesis of 2,4,6-Triarylpyridines.
DBH (10 mol %) was added to a mixture of the aldehyde (1 mmol), acetophenone
(2 mmol), and ammonium acetate (0.154 g, 2 mmol) in a 10 mL flask at room tempera-
ture. The temperature was then raised to 120ꢀC and maintained for the appropriate time
(see Table 2) with stirring. After the completion of the reaction as indicated by TLC (hex-
ane-ethyl acetate, 4:1), hot EtOH (96%, 1 ml) was added and the mixture stirred for
5 min. Then the catalyst was filtered off and the filtrate was poured into crushed ice. The
solid product, which separated, was collected and recrystallized from ethanol (96%,
3 ml) to afford the pure 2,4,6-triarylpyridine (3a-t).
Acknowledgments
We are thankful to Hakim Sabzevari (Research Council) partial supported of this work.
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